7. PROJECT SUMMARY/ABSTRACT This proposal requests 5 years of support to train Dr. Forgacs to be an independent clinical investigator, with a research focus on promoting recovery after severe brain injury in acute care settings. To advance towards these goals, Dr. Forgacs? research will characterize specific circuit-level neurobiological mechanisms important to recovery of consciousness in patients with severe anoxic brain injury after cardiac arrest. A K23 award will enable him to carry out this research in the setting of a cohesive training program concentrating on specific translational research aspects of neurological recovery of patients in acute care settings, neuroimaging in clinical research and detailed training in analysis of complex multivariate data obtained during multi-modal monitoring. These career development goals will be pursued via customized tutorial interactions with his primary mentor, Dr. Nicholas Schiff and a mentoring team including Drs. Jan Claassen, Henning Voss and Jonathan Victor. The central hypothesis of the current proposal is that a specific circuit, the anterior forebrain mesocircuit (AFM) underlies the recovery of consciousness after cardiac arrest. The AFM consists of widespread connections from the central thalamus to the frontal cortex and striatum, which is modified via inputs from the basal ganglia, and has been linked to recovery of consciousness in patients with chronic disorders of consciousness primarily as a result of a traumatic brain injury. Functional integrity of AFM related to output from the central thalamus can be measured using EEG spectral analysis and 18FDG-PET. Dr. Forgacs will test this hypothesis in two patient populations with limited evidence of conscious awareness, an acute cohort (patients in the ICU after cardiac arrest), and a chronic cohort (patients who survived cardiac arrest for longer than 6 months). Specific Aim 1 will involve the acute cohort of patients and will investigate fronto-central spectral EEG features of AFM integrity in relation to bedside assessments of consciousness. Specific Aim 2 will involve the chronic cohort of patients and in addition to EEG spectral analysis this aim will also utilize 18FDG-PET and functional MRI or EEG-based assessments that are not feasible in the acute care settings. This will allow further characterization of AFM using metabolic activity patterns of AFM and correlate it with fronto-central EEG spectral features. Furthermore, fMRI/fEEG methods allow assessment of the possibility of covert conscious awareness by demonstrating motor imagery responses to auditory command in patients with limited bedside exam secondary to injury of the motor system. Studies in the chronic cohort will provide detailed characterization of these patients and thus yield further insight into the role of AFM in mechanisms of the recovery of consciousness after cardiac arrest. The outcomes of these aims are expected to provide a detailed mechanistic model of recovery mechanisms after cardiac arrest; thereby providing a basis for selecting patients with better chances for good recovery and for developing new therapeutic interventions based on neurobiological principles.